Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S. The core motor symptoms of PD are attributable to the degeneration of the mesencephalic dopaminergic neurons and alterations in the activity of neurons in the basal ganglia. In PD patients and in primate PD models, neurons in two key nuclei of the basal ganglia - the external segment of the globus (GPe) and the subthalamic nucleus (STN) - spike in synchronous, high frequency rhythmic bursts.This pathophysiological activity is thought to be responsible for bradykinesia, akinesia and rigidity in PD patients.Theoretical studies suggest that autonomous pacemaking in GPe neurons counter-balances the natural tendency of the reciprocally connected, STN-GPe network to transition into the pathological synchronous, rhythmic bursting seen in PD. The model that has dominated the field for the last two decades has assumed that following DA depletion there is an elevation in striatopallidal GABAergic inhibitory input to the GPe, leading to a suppression of this autonomous activity. In the course of pursuing this hypothesis, we discovered that DA depletion induces a change in the intrinsic properties of GPe neurons that results in the loss of autonomous pacemaking. Moverover, this loss appears to be attributable to the down-regulation of a single ion channel subunit (HCN2). It is our central hypothesis that the loss of autonomous pacemaking is responsible for the emergence of synchronous rhythmic bursting of the STN-GPe network in PD and that reversing this adaptation will not only diminish the pathophysiology in this network, it will alleviate the motor symptoms ofPD. This project blends the skills of the labs of Drs. Surmeier, Wilson, Kita and Osten to pursue four specific aims addressing the basic mechanisms underlying this 'silencing' in rodent and monkey models of PD as well as strategies that could be used in PD patients to correct the deficit. Our aims are: 1) to characterize the mechanisms governing the rate and regularity of autonomous pacemaking in GPe neurons and their adaptation in rodent PD models (Wilson); 2) to characterize the mechanisms governing the suppression of pacemaking in GPe neurons in rodent PD models and to develop a means for its restoration (Surmeier, Osten, Kita); 3) to characterize subthalamo-pallidal glutamatergic signaling in rodent PD models and its potential role in suppression of pacemaking (Surmeier); 4) to characterize the role of subthalamo-pallidal synaptic signaling in controlling GPe activity and its adaptations in a monkey model of PD (Kita). Lay summary: These studies are aimed at correcting dysfunctional brain activity in late stage PD. The successful attainment of our aims could not only provide a novel, gene therapy for late stage PD but open new avenues for pharmacological treatment.